Hearing loss is a serious handicap which affects millions of people. Hearing impairments can be attributed to a wide variety of causes, including infections, mechanical injury, loud sounds, aging, and chemical-induced ototoxicity that damages neurons and/or hair cells of the peripheral auditory system.
The peripheral auditory system consists of auditory receptors, hair cells in the organ of Corti, and primary auditory neurons, the spiral ganglion neurons in the cochlea. The activity of the synapse between the inner hair cells (IHCs) and the type II afferent dendrites is modulated by the lateral olivocochlear (LOC) efferent fibers (Eybalin M, (1993) Neurotransmitters and neuromodulators of the mammalian cochlea. Physiol Rev 73: 309-373; Eybalin M, Pujol R, (1989) Cochlear neuroactive substances. Arch Otorhinolaryngol 246: 228-234; Puel J-L, (1995) Chemical synaptic transmission in the cochlea. Prog Neurobiol 47: 449-476).
Ototoxicity is caused by drugs or chemicals that damage the inner ear or the vestibulocochlear nerve, which sends balance and hearing information to the brain from the inner ear. Ototoxicity may result in temporary or permanent losses of hearing, balance, or both. Substances that may cause ototoxicity include antibiotics, chemotherapy drugs, environmental chemicals, loop diuretics, aspirin and quinine products.
Rasagiline, R(+)-N-propargyl-1-aminoindan, is a potent second generation monoamine oxidase (MAO) B inhibitor (Finberg J P, Youdim M B, (2002) Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours. Neuropharmacology 43(7):1110-8). Rasagiline mesylate in a 1 mg tablet is commercially available as monotherapy or as an adjunct for the treatment of idiopathic Parkinson's disease as Azilect® from Teva Pharmaceuticals Industries, Ltd. (Petach Tikva, Israel) and H. Lundbeck A/S (Copenhagen, Denmark). See, e.g. AZILECT®, Physician's Desk Reference (2006), 60th Edition, Thomson Healthcare. Recent studies have demonstrated that, in addition to its MAO-B inhibitor activity, rasagiline possesses potent neuroprotective activity demonstrated by in vitro and in vivo experiments. Neuroprotection by rasagiline was achieved in animal models of closed head trauma (Huang W, Chen Y, Shohami E, Weinstock M. (1999) Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse. Eur J. Pharmacol. 366(2-3):127-35), global focal ischemia (Speiser Z, Mayk A, Eliash S, Cohen S. (1999) Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemia in the rat. 106 (7-8) 593-606) and MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity (Sage et al. 2001, 2003) as well as transgenic model of amyotrophic lateral sclerosis (Waibel S. et al. (2004) Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model. 251 (9) 1080-1084) and 6-OHDA(6-hydroxydopamine) model of Parkinson's disease (Blandini, F. et al. (2004) Neuroprotective effect of rasagiline in a rodent model of Parkinson's disease. Exp Neurol. 2004 June; 187(2):455-9). Cell culture experiments have shown that rasagiline potently suppresses apoptotic cell death initiated by mitochondria (Youdim M B H, et al., (2001) Rasagiline (N-propargyl-1R(+)-aminoindan), a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br. J. Pharmacol., 132:500-6; Akao Y. et al. (2002) Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan. 82 (4) 913-923) by preventing preapoptotic swelling of mitochondria, caspase 3 activation, activation of nuclear PARP(poly ADP ribose polymerase)-1, translocation of GADPH(glyceraldehydes-3-phosphate dehydroxenase), and nucleasomal DNA fragmentation (Youdim M B H and Weistock M. (2001) Molecular Basis of Neuroprotective Activities of Rasagiline and the Anti-Alzheimer Drug TV3326 [N-Propargyl-(3R) Aminoindan-5-YL)-Ethyl Methyl Carbamate]. Cell. Mol. Neurobio. 21(6) 555-573; Youdim M B H et al. (2003) Neuroprotective Strategies in Parkinson's Disease: An Update on Progress. CNS Drugs. 17(10):729-762; Bar-am et al. (2004) Regulation of protein kinase C by the anti-Parkinson drug, MAO-B inhibitor, rasagiline and its derivatives, in vivo. Journal of Neurochemistry 89 (5), 1119-1125; and Weinreb O. et al. (2004) Neurological mechanisms of green tea polyphenols in Alzheimer's and Parkinson's diseases. The Journal of Nutritional Biochemistry, Volume 15, Issue 9, Pages 506-516). Further, rasagiline induces increase of the anti-apoptotic Bcl-2 and Bcl-xL expression parallel to downregulation of proapoptotic Bad and Bax (Youdim M B H et al. (2003) The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. Biochem Pharmacol. 66(8):1635-41; Yogev-Falach et al. (2003) Amyloid Processing and Signal Transduction Properties of Antiparkinson-Antialzheimer Neuroprotective Drugs Rasagiline and TV3326. Annals of the New York Academy of Sciences 993:378-386). Recent evidence from a delayed-start design study in Parkinson's Disease has suggested potential disease-modifying efficacy of rasagiline also in a clinical setting (Parkinson Study, G, A controlled, randomized, delayed-start study of rasagiline in early Parkinson's disease, Arch. Neurol. (2004) 61 (4): 561-6).
Whether rasagiline has positive effects on the peripheral auditory system has not been heretofore investigated.